The present invention relates to certain novel spiro derivatives of Formula I, IA, IB, II, IIA, III, or IIIA as depicted below, pharmaceutical formulations containing them, and their uses as therapeutic agents, and syntheses therefore. Their uses as therapeutic agents that may act as lipoxygenase inhibitors include, but are not limited to, prevention or treatment of diseases involving apoptosis in cancer cells; diseases involving hypoxia or anoxia; diseases involving inflammation; disorders of the airways; diseases involving central nervous system (CNS) disorders, neurodegeneration and neuroinflammation; and diseases involving the autoimmune system.
The use of compounds having a chroman moiety as lipoxygenase inhibitors has been disclosed, for example, in U.S. Pat. No. 5,059,609; U.S. Pat. No. 4,950,684; U.S. Pat. No. 5,015,661; U.S. Pat. No. 4,780,469; U.S. Pat. No. 5,591,772; U.S. Pat. No. 5,925,673; U.S. Pat. No. 5,250,547; U.S. Pat. No. 5,393,775; U.S. Pat. No. 4,814,346; U.S. Pat. No. 5,939,452, U.S. Pat. No. 6,051,601; U.S. Pat. No. 6,117,874; and U.S. Pat. No. 6,133,286.
Arachidonic acid is an essential fatty acid that exists within the cell membrane and can be released from phospholipids by the action of phospholipase. The released arachidonic acid is metabolized through three major enzymatic pathways, i.e. the lipoxygenase pathway, to form substances such as prostaglandins which are associated with inflammatory responses, and thromboxanes which are associated with the formation of thrombus, or leukotrienes which induce allergic reactions.
Lipoxygenases are non-heme iron-containing enzymes that catalyze the oxidation of polyunsaturated fatty acids and esters thereof. They were originally classified based on their substrate specificity for insertion of molecular oxygen into arachidonic acid at carbon positions 5, 12 and 15, but more recently a phylogenetic classification is being used. This separates the mammalian enzymes in four main subtypes, 5-Lipoxygenase, 12/15-Lipoxygenases, platelet 12-Lipoxygenases and epidermis-type lipoxygenases. The 12/15 family of lipoxygenases includes two sub-families with a high degree of sequence homology, the reticulocyte 15-Lipoxygenases (found in rabbit and humans) and the leukocyte
12-Lipoxygenases (found in mouse, pig, rat, and rabbit). This type of lipoxygenase shares more homology to reticulocyte 15-Lipoxygenase and leukocyte 12-Lipoxygenase, than to platelet 12-Lipoxygenases.
It is believed that oxidative metabolites of the 12/15-Lipoxygenase or the 15-Lipoxygenase cascade have been implicated in the potentiation of thrombin induced platelet activation (Setty et al. Blood, (1992), 2765-2773); in the progression of various cancers (Kelavkar et al, Curr. Urol. Rep. Vol. 3 no. 3 (2002) pp. 207-214) and related pathologies (Tisdale et al., Science Vol. 289 no. 5488 (2000) pp. 2293-4). It has also been shown that treatment with a 15-Lipoxygenase inhibitor suppresses atherogenesis in rabbits fed a high-fat diet (Bocan et al., Atherosclerosis, Vol. 136 (1998) pp. 203-16). There is increasing evidence that certain lipoxygenase enzymes are involved in the pathogenesis and acceleration of atherosclerosis by inducing oxidation of LDL to its atherogenic form (Sparrow, C. P., et al., J. Lipid Res. Vol. 29 (1988) pp. 745-753. and Steinberg, D., New Eng. J. Med. Vol. 320 (1989) pp. 915-924). It has also been reported that 12-Lipoxygenase enzyme plays a role in mediating angiotensin II induced vascular and adrenal actions (Natarajan, R., et al., Endocrinology Vol. 131 (1992) pp. 1174-1180). Recent studies (Klein, R. et al., Science Vol. 303 no. 5655 (2004) 329-332) have also shown the role of 15-Lipoxygenase enzyme in the regulation of bone density.
The enzyme 5-Lipoxygenase converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes. Evidence of the role of leukotrienes in the pathology of certain diseases has been described, for example in Cloud et al., J. Allergy Clin. Immunol., Vol. 79 (1987) pp. 256 (asthma); Turnbull et al., Lancet II, (1977) pp. 526-9 (chronic bronchitis); Cromwell et al., Lancet II, (1981) pp. 164-5 (cystic fibrosis); Davidson et al., J. Pharm. Pharmacol. Vol. 34 no. 61 (982) pp. 410 (rheumatoid arthritis); Rae et al., Lancet. Vol. 2 no. 8308 (1982) pp. 1122-4. Cook et al., J. Pharmacol. Exp. Ther., 235, (1985) pp. 470-474 (cardiovascular conditions); Tsuji et al., Biochem. Pharmacol. Vol. 55 no. 3: (1998); pp. 297-304 (dermatitis such as psoriasis).
It has also been shown in co-owned U.S. application Ser. No. 11/251,423 filed Oct. 13, 2005, titled Methods for Treating Diabetes, herein incorporated by reference in its entirety, that dual 5-Lipoxygenase and 12/15-Lipoxygenase inhibitors or 5-Lipoxygenase and 15-Lipoxygenase inhibitors are superior in the prevention of treatment of subjects susceptible to diabetes, are able to improve glucose control in animal models of diabetes, and have demonstrated a significant lowering of the baseline serum glucose levels compared to selective 5-Lipoxygenase, 15-Lipoxygenase and 12/15-Lipoxygenase inhibitors.
The compositions, formulations and methods of this invention are particularly applicable in preventing and/or treating diseases or disorders mediated, at least in part, by one or more lipoxygenase enzymes, such as 5-Lipoxygenase enzyme and/or 12/15-Lipoxygenase enzyme.